Trajectory of plasma lipidomes associated with the risk of late-onset Alzheimer’s disease pathogenesis: a longitudinal study in the ADNI cohort

Comprehensive lipidomic studies have demonstrated strong cross-sectional associations between the blood lipidome and late-onset Alzheimer’s disease (AD) and its risk factors. However, the longitudinal relationship between the lipidomic variations and progression of AD remains unknown. Here, we employed longitudinal lipidomic profiling on 4,730 plasma samples from 1,517 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to investigate the temporal evolution of lipidomes among diagnostic groups. At baseline, there were 1,393 participants including 437 cognitively normal (CN), 713 with mild cognitive impairment (MCI), and 243 AD cases. During follow up, 329 individuals (29 CN and 300 MCI) developed clinical AD (AD converters). We developed an AD-CN classification model to stratify the non-converting MCI group into AD-like and non AD-like MCI based on their lipidomics profiles at baseline. Longitudinal analysis identified associations between the change in ether lipid species (including alkylphosphatidylcholine, alkenylphosphatidylcholine, lysoalkylphosphatidylcholine, and lysoalkenylphosphatidylcholine) in converters relative to non-converting CN and MCI groups. Further, the AD-CN model efficiently classified MCI into low AD risk and high AD risk, with the high AD risk group having two times higher risk of conversion to AD than the low risk group. These findings suggest that the lipidomic profile can serve as a potential biomarker to identify individuals at higher risk for progressing to AD. ### Competing Interest Statement Dr. Kaddurah-Daouk is an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix. Prof. Meikle leads the provisional patent "METHODS OF ASSESSING ALZHEIMER'S DISEASE" on the development of AD-CN risk scores that has been filed with the Serial No. 63/463,808. Other authors have declared that no conflict of interest exists. ### Funding Statement Support was provided by the National Health and Medical Research Council of Australia (# 1101320 and 1157607). KH is supported by an NHMRC Investigator grant (GNT1197190). This work was also supported in part by the Victorian Government's Operational Infrastructure Support Program. The data available in the AD Knowledge Portal would not be possible without the participation of research volunteers and the contribution of data by collaborating researchers. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ([www.fnih.org][1]). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Metabolomics data is provided by the Alzheimer's Disease Metabolomics Consortium (ADMC) and funded wholly or in part by the following grants and supplements thereto: NIA R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, U19AG063744 and FNIH: #DAOU16AMPA awarded to Dr. Kaddurah-Daouk at Duke University in partnership with a large number of academic institutions. As such, the investigators within the ADMC, not listed specifically in this publication's author's list, provided data along with its pre-processing and prepared it for analysis, but did not participate in analysis or writing of this manuscript. A complete listing of ADMC investigators can be found at: . Data on lipidome was generated at Baker Heart and Diabetes Institute, a member of ADMC. Details on the lipid profiling technologies are described at: (). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study data used are available and were downloaded from the ADNI data repository ([www.loni.usc.edu/ADNI/][2]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The results published here are in whole or in part based on data obtained from the AD Knowledge Portal. ADNI associated data is also available from the Laboratory of Neuro Imaging Image and Data Archive at . . [1]: http://www.fnih.org [2]: http://www.loni.usc.edu/ADNI/